Qiao Liang, Dai Yun, Gu Qing, Chan Kwok Wah, Ma Juan, Lan H Y, Zou Bing, Rocken Christoph, Ebert Matthias P A, Wong Benjamin C Y
Department of Medicine, University of Hong Kong, Queen Mary Hospital, Hong Kong.
Cancer Lett. 2008 Sep 18;268(2):260-71. doi: 10.1016/j.canlet.2008.04.003. Epub 2008 May 13.
We investigated whether the anticancer effect of a combination of XIAP down-regulation and PPAR gamma activation on colon cancer is PPARgamma receptor dependent. HCT116-XIAP(+/+) cells and HCT116-XIAP(-/-) cells were treated with troglitazone or 15-deoxy-Delta(12,14)-prostaglandin J2 (15-PGJ2) with or without prior exposure to PPARgamma inhibitor GW9662. Cell proliferation and apoptosis was evaluated. Athymic mice carrying HCT116-XIAP(-/-) cells-derived tumors were treated with troglitazone in the presence or absence of GW9662. Inhibition of cell proliferation and induction of apoptosis by troglitazone and 15-PGJ2 were more prominent in HCT116-XIAP(-/-) cells. PPARgamma ligand-induced growth inhibition, apoptosis, caspase and PARP cleavage could not be blocked by GW9662. Troglitazone significantly retarded growth of xenograft tumors and this effect was not blocked by GW9662. Marked apoptosis and an up-regulation of E-cadherin were observed in xenograft tumor tissues, and GW9662 did not affect these effects. Thus, a combination of XIAP down-regulation and PPARgamma ligands exert a significant anticancer effect in colon cancer via a PPARgamma independent pathway.
我们研究了X连锁凋亡抑制蛋白（XIAP）下调与过氧化物酶体增殖物激活受体γ（PPARγ）激活联合应用对结肠癌的抗癌作用是否依赖于PPARγ受体。用曲格列酮或15-脱氧-Δ12,14-前列腺素J2（15-PGJ2）处理HCT116-XIAP（+/+）细胞和HCT116-XIAP（-/-）细胞，且处理前细胞有或没有预先接触PPARγ抑制剂GW9662。评估细胞增殖和凋亡情况。对携带HCT116-XIAP（-/-）细胞来源肿瘤的裸鼠在有或没有GW9662存在的情况下用曲格列酮进行处理。曲格列酮和15-PGJ2对细胞增殖的抑制及对凋亡的诱导在HCT116-XIAP（-/-）细胞中更显著。GW9662不能阻断PPARγ配体诱导的生长抑制、凋亡、半胱天冬酶和聚（ADP-核糖）聚合酶（PARP）的裂解。曲格列酮显著延缓异种移植肿瘤的生长，且这种作用不能被GW9662阻断。在异种移植肿瘤组织中观察到明显的凋亡和E-钙黏蛋白的上调，且GW9662不影响这些作用。因此，XIAP下调与PPARγ配体联合应用通过一条不依赖PPARγ的途径在结肠癌中发挥显著的抗癌作用。
